Project Summary/Abstract The brain is wired to integrate data from multiple sensory inputs, and is highly dynamic and amenable to plasticity and reorganization. Our long-term goal is to understand the molecular mechanisms that coordinate different brain circuits and govern brain-wide plasticity. In particular, we are interested in cross-modal plasticity that occurs following the loss of a sensory modality, due to disease or injury, and leads to enhanced performance of remaining sensory modalities. However, in addition to positive adaptive outcomes, cross-modal plasticity might also have negative impacts on sensory acuity and precision. Cross-modal plasticity has been studied extensively at the macroscopic level of brain structures in mammalian brains. In contrast, molecular pathways that produce opposing outcomes upon sensory deprivation are much less known. We have recently discovered a form of cross-modal plasticity in the simple nervous system of C. elegans, which presents an opportunity to genetically trace the molecular basis for cross-modal plasticity. Our data show that loss of body touch sensation increases olfactory acuity towards a certain class of odors. The underlying molecular pathway shares striking similarities with analogous mammalian systems. We were able to counteract the observed plastic changes using a synaptic engineering approach. We also found that in parallel to the adaptive increase in olfactory performance, loss of body touch sensation resulted in a concomitant decrease in olfaction towards a second group of attractive odors and to a reduced response to mechanical stimulation of the nose. Here, we propose to explore the molecular constituents of cross-modal plasticity using genetic manipulations in C. elegans. Our goal is to identify system- wide interactions with both positive and negative impacts across multiple sensory modalities. We will address several fundamental questions. What are the molecular determinants that lead to opposite behavioral outcomes? Are they independent or do they interact? We will examine these questions using genetics, behavioral assays, calcium imaging, optogenetics, and synaptic engineering. Delving into the molecular mechanisms underlying cross-modal plasticity and especially into the manner in which various forms of cross-modal plasticity interact will provide new molecular insights into plasticity from a system-wide perspective, and promises to introduce potential avenues for intervention in sensory loss disorders.